Abstract Intestinal transplantation (ITx) has emerged as a key, but under-utilized and under-studied, therapeutic option for patients suffering from intestinal failure. Specifically, while an estimated 40,000 patients could benefit from ITx, a mere 141 ITx transplants were performed in the United States in 2015; the country's lowest volume solid organ transplant. This low volume is due to poor patient and allograft survival after ITx when compared to other fields of solid organ transplantation as this transplant is associated with the transplantation of the largest immune cell and microbial load of any solid organ. Because there is a high risk of allograft enteropathy/ immunological graft loss, strong regimens of generalized immunosuppression are typically applied, which lead to high morbidity and mortality. The result is a catch-22: if ITx is performed, the risk of rejection is high, which leads to over-immunosuppression, which results in complications and high treatment costs, which dissuades ITx from being offered in the first place. To untangle this catch-22 and unleash the potential of ITx, this project will leverage the fact that we are the leading ITx center in the country and lay the groundwork for a targeted immunotherapy approach to prevent/ control allograft enteropathy with minimization of generalized immunosuppression. Preliminary data has revealed that both the adaptive and innate immune systems are key players in stable allograft function and allograft enteropathy and as such, this project's three specific aims will focus on both systems: 1. To determine the roles and mechanisms of proinflammatory Th17 and protective regulatory T cell (Treg) responses in human ITx recipients with stable allograft function versus enteropathy 2. To determine the roles and mechanisms of proinflammatory type 1 innate lymphoid cell (ILC1) and protective type 3 innate lymphoid cell (ILC3) responses in human ITx recipients with stable allograft function versus enteropathy 3. To elucidate the crosstalk between the master regulators NOD2 (antimicrobial sensor) and CD39 (purinergic signaling) and innate and adaptive immune responses in human ITx recipients with stable allograft function versus enteropathy These three aims will lay the foundation for improving outcomes and quality of life for several patient groups: (A) patients who are on home-based TPN regimens could be considered for ITx, ideally before complications worsen that jeopardize the outcomes of ITx; (B) new and past recipients of ITx could avoid the life threatening complications from generalized immunosuppression, which will be especially beneficial for children who receive ITx in their earliest years of life; and (C) patients suffering from IBD could benefit from new therapeutic insights as we hypothesize that IBD is influenced by similar factors that modulate ITx enteropathy.